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CLEC5A is critical for dengue-virus-induced lethal disease

Nature volume 453, pages 672–676 (2008)Cite this article

Abstract

Dengue haemorrhagic fever and dengue shock syndrome, the most severe responses to dengue virus (DV) infection, are characterized by plasma leakage (due to increased vascular permeability) and low platelet counts1,2. CLEC5A (C-type lectin domain family 5, member A; also known as myeloid DAP12-associating lectin (MDL-1))3 contains a C-type lectin-like fold similar to the natural-killer T-cell C-type lectin domains and associates with a 12-kDa DNAX-activating protein (DAP12)4 on myeloid cells. Here we show that CLEC5A interacts with the dengue virion directly and thereby brings about DAP12 phosphorylation. The CLEC5A–DV interaction does not result in viral entry but stimulates the release of proinflammatory cytokines. Blockade of CLEC5A–DV interaction suppresses the secretion of proinflammatory cytokines without affecting the release of interferon-α, supporting the notion that CLEC5A acts as a signalling receptor for proinflammatory cytokine release. Moreover, anti-CLEC5A monoclonal antibodies inhibit DV-induced plasma leakage, as well as subcutaneous and vital-organ haemorrhaging, and reduce the mortality of DV infection by about 50% in STAT1-deficient mice. Our observation that blockade of CLEC5A-mediated signalling attenuates the production of proinflammatory cytokines by macrophages infected with DV (either alone or complexed with an enhancing antibody) offers a promising strategy for alleviating tissue damage and increasing the survival of patients suffering from dengue haemorrhagic fever and dengue shock syndrome, and possibly even other virus-induced inflammatory diseases.

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Figure 1: DV interacts with CLEC5A.
Figure 2: CLEC5A is essential for DV-induced DAP12 phosphorylation, but not for DV replication.
Figure 3: CLEC5A is critical for DV-mediated secretion of TNF-α but not that of IFN-α.
Figure 4: Anti-mCLEC5A mAbs prevents DV-induced vascular leakage and lethality in STAT1-deficient mice.

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Acknowledgements

We thank W.-C. Yeh, C. Milner and J. Paulson for critical comments; N.-J. Chen, C.-H. Lin, Y-L. Lee and J.-J. Liang for technical assistance. Resources and collaborative efforts were provided by the RNAi Consortium, Academia Sinica, Taiwan, and the Consortium for Functional Glycomics funded by the National Institute of General Medical Sciences (GM62116). This work was supported mainly by the National Research Program for Genomic Medicine, National Science Council, Taiwan (NSC-95-3112-B-010-0171 and NSC 96-3112-B-010-2), and in part by the National Yang-Ming University, Taiwan (96A-D-D132 from the Ministry of Education), Taipei Veterans General Hospital (V97S5-001), and Academia Sinica.

Author Contributions S.-T.C. designed, performed and analysed experiments, and wrote the paper. Y.-L.L. designed, analysed experiments and wrote the paper. M.-T.H., M.-F.W. and S.-C.C. performed experiments. H.-Y.L., C.-K.L. and T.-W.C. provided materials and reagents. C.-H.W. analysed experiments. S.-L.H. designed and analysed experiments, and wrote the paper.

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Authors and Affiliations

  1. Department and Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan

    Szu-Ting Chen, Ming-Ting Huang, Ming-Fang Wu, Shih-Chin Cheng & Shie-Liang Hsieh

  2. Institute of Biomedical Sciences, and,,

    Yi-Ling Lin

  3. Genomics Research Center, Academia Sinica, Taipei 115, Taiwan,

    Yi-Ling Lin, Chi-Huey Wong & Shie-Liang Hsieh

  4. Department of Microbiology and Immunology, National Cheng Kung University, Tainan 701, Taiwan

    Huan-Yao Lei

  5. Institute of Immunology, National Taiwan University, Taipei 100, Taiwan

    Chien-Kuo Lee

  6. Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan

    Tzyy-Wen Chiou

  7. Immunology Research Center, National Yang-Ming University & Taipei Veterans General Hospital, Taipei 112, Taiwan

    Shie-Liang Hsieh

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Chen, ST., Lin, YL., Huang, MT. et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453, 672–676 (2008). https://doi.org/10.1038/nature07013

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